Coronavirus COVID-19 Vaccines

RECENT UPDATES

• BioNTech/Pfizer BNT162 vaccine
  • In correspondence to the editor published in NEJM the vaccine was found to be approximately two-thirds less effective at neutralizing the SARS-CoV-2 virus modified to have spike protein mutations similar to the B.1.351 (South Africa) variant.[3] [February 17]
  • Results from a pre-print posted to bioRxiv indicate the vaccine is effective against the B.1.1.7 variant of SARS-CoV-2 first identified in the UK.[4] [February 17]
  • Vaccine approved for Emergency Use in the UK[5] [December 2], Canada[6] [December 9], the U.S.[7] [December 11], and the EU.[8] [December 22]
  • Phase 3 trial concluded showing reduction of COVID-19 infection by 95% in vaccine recipients.[9] In 43,661 participants, 170 confirmed cases of COVID-19 were evaluated, with 162 observed in the placebo group versus 8 in the vaccine group. [November 18]
  • Phase 3 study interim results reported in a company press release showed reduction of COVID-19 infection by 90% in vaccine recipients.[10] Results have not yet been published in a peer-reviewed journal. Study enrolled 43,538 participants to date and the first interim efficacy analysis was conducted when 94 COVID-19 cases were confirmed. The case split between vaccinated individuals and those who received the placebo indicated a vaccine efficacy rate above 90%, at 7 days after the second dose (given at day 28). No serious side effects were reported. The trial is continuing to enroll and is expected to continue through the final analysis when a total of 164 confirmed COVID-19 cases have accrued. [November 9]
  • Phase 1/2 trial published in Nature[11] showed that 60-person subset in immunized individuals generate a robust SARS-CoV-2-sepcific antibody and cellular mediated immune response which suggests multiple mechanisms with potential to protect against COVID-19. [September 30]
  • Phase 1/2 trial results published in Nature[12] showing that in 36 healthy adults 18–55 who received 2 doses of vaccine separated by 21 days developed RBD-binding and neutralizing antibodies higher than with natural infection. Mild to moderate side effects were common. [August 12; preprint published July 1]
  • U.S. government ordered 100 million doses of BNT162 for $1.95 billion as part of the U.S. Warp Speed program. A Phase 2b/3 safety and efficacy trial for the vaccine begins in late July 2020.[13][July 22]
• University of Oxford / AstraZeneca AZD1222 vaccine
  • South Africa suspends use of vaccine because preliminary results from study of ~2,000 volunteers in South Africa showed 2-dose regimen was only 22% effective against mild-moderate COVID-19 infection from the B.1.351 coronavirus variant first identified in South Africa.[14] [February 8]
  • Study published on a Lancet pre-print server[15] revealed vaccine efficacy of 67% overall with no hospitalizations in the vaccine group 22 days after the first dose. Efficacy appeared to be enhanced (82%) if the second dose was given 12 weeks or more after the first dose. The study also showed that transmission of the virus by vaccine recipients, as measured by weekly PCR tests, was reduced by 67% after a single dose and 50% after the two dose regimen. [February 2]
  • Vaccine approved for Emergency Use in the UK[16] [December 30], EU[17] [January 29], and other countries.
  • Phase 3 trial interim results reported in the Lancet.[18] [December 8]
  • Phase 3 trial interim results reported in a company press release showed reduction of COVID-19 infection by 70% in vaccine recipients.[19]Study enrolled more than 23,000 participants to date in the UK and Brazil and the first interim efficacy analysis was conducted when 131 COVID-19 cases were confirmed beginning two weeks after the second dose. One dosing regimen showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen showed 62% efficacy when given as two full doses at least one month apart (for a combined average efficacy of 70%). No hospitalizations for severe COVID-19 cases were reported in the group receiving a vaccine. Based on these results, the company intends to submit for an Emergency Use Authorization (EUA) with the World Health Organization in coming weeks. [November 23]
  • Phase 3 trial resumed in the US after safety review by the FDA.[20] [October 23]
  • Phase 3 trial resumed in the UK[21] (where the case of transverse myelitis occurred) but not yet in the United States, due to safety concerns at the NIH and FDA. [September 12]
  • Phase 3 trial paused[22] due to a trial participant developing a serious neurological event, thought to be transverse myelitis.[23] Transverse myelitis is a rare disorder of the spinal cord that, like Guillain-Barré syndrome, can be triggered by certain viral infections, including SARS-CoV-2 itself. Investigators and the U.S. National Institutes of Health have pledged to fully investigate whether this case could be associated with the vaccine. [September 9]
  • Preclinical study in rhesus macaques reported in Nature[24] showed that a single vaccination with ChAdOx1 nCoV-19 is effective in preventing damage to the lungs upon high dose challenge to both upper and lower respiratory tract with SARS-CoV-2; there was also no evidence of immune-enhanced disease in vaccinated animals. However, in regard to possible infectivity, nasal shedding of the virus was not significantly different between vaccinated and control animals. [July 30]
  • Phase 1/2 trial published in Lancet[25] showed that in adults age 18–55 a single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunization augmenting neutralizing antibody titres. No serious adverse effect were reported; mild-moderate side effects were common. [July 20]
  • Phase 3 trials that are underway in Brazil, South Africa, and the UK.
• Gamaleya Research Institute Gam-COVID-Vac vaccine
  • Phase 3 trial interim results reported in the Lancet showed reduction of COVID-19 infection by 92% in vaccine recipients.[26] Study enrolled ~20,000 participants > age 18 in Moscow and the first interim efficacy analysis was conducted when 78 COVID-19 cases were confirmed 21 days after the first dose (the day of dose 2). Most reported adverse events were mild. 45 (0.3%) of 16,427 participants in the vaccine group and 23 (0.4%) of 5,435 participants in the placebo group had serious adverse events; none were considered associated with vaccination as confirmed by the independent data monitoring committee. [February 2]
  • Phase 1/2 trial results published in Lancet[27] showed 76 adults receiving one of two vaccine types (rAd26-S or rAd5-S) either alone or with a booster at 21 days generated both neutralizing and specific IgG antibodies. Mild-moderate side effects (pain at injection site, fever, headache, myalgia) were common, but no major side effects were reported. [September 4]
  • Phase 1 trials of this vaccine were registered in June 2020 but no results have have been published in the scientific literature. Despite this, Russian President Vladimir Putin announced regulatory approval of the vaccine (to be called "Sputnik V" in foreign markets). Mass vaccination in Russia is expected to start in October 2020.[28][August 11]
• Johnson & Johnson/Janssen Ad26.COV2-S vaccine
  • Phase 3 trial interim results reported in a company press release showed reduction of COVID-19 infection by 66% in vaccine recipients.[29] Study enrolled nearly 44,000 participants and the first interim efficacy analysis was conducted when 468 COVID-19 cases were confirmed 28 days after a single-dose vaccine. The onset of protection was observed as early as 14 days. Level of protection varied by geography likely due to different circulating SARS-CoV-2 strains: effectiveness was 72% in the US, 66% in Latin America, and 57% in South Africa. [January 29]
  • Trials resumed in the US after safety review by the company and an independent Data Safety Monitoring Board (DSMB) found no evidence that the vaccine candidate caused the medical event experienced by one study partipant.[30] [October 23]
  • All trials of this vaccine paused (including Phase 3 trial)[31] due to an unexplained illness in a study participant. The company and a DSMB are investigating. [October 12]
  • Phase 3 trial (ENSEMBLE) begun with 60,000 partipants from mulitple country.[32] [September 23]
  • Preclinical study in rhesus macaques reported in Nature[33] showed a single dose of the adenovirus serotype 26 (Ad26) vector-based vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge. [July 30]
  • Phase 1/2 trial began in late July.
  • The company received Warp Speed funding of $456 million for pre-clinical and Phase 1 clinical trials. [March 30]
• Novavax NVX-CoV2373 vaccine
  • Phase 3 trial interim results reported in a company press release showed reduction of COVID-19 infection by 89% in vaccine recipients.[34] Study enrolled ~15,000 participants and the first interim efficacy analysis was conducted when 62 COVID-19 cases were confirmed 7 days after a second vaccine dose. Preliminary analysis indicated that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain. [January 28]
  • Phase 3 trial begins with 10k participants in the UK.[35] A similar trial is expected to start in the U.S in October. [September 24]
  • Phase 1/2 trial published in New England Journal of Medicine[36] showed that in 106 healthy adults age 18–59 who received two doses spaced 21 days apart had robust immune responses with both IgG and neutralization antibodies 4-fold higher than seen in natural infection. Mild-moderate side effects were common and greater local and systemic reactogenicity occurred with the second dose. [September 2]
  • Received U.S. Warp Speed funding for protein-based vaccine development and clinical trials.[37][July 7]
• Moderna mRNA-1273 vaccine
  • In vitro neutralization studies not yet published in a peer-reviewed journal show vaccine activity against emerging strains of SARS-CoV-2.[38],[4] Moderna vaccine produced neutralizing titers against emerging variants including B.1.1.7 (first identified in the UK) and B.1.351 (first identified in South Africa [SA]). The vaccine produced neutralizing antibodies against B.1.1.7 (UK) at levels comparable to prior variants but neutralization antibody induction was 6-fold lower in the B.1.351 (SA) variant. Despite this reduction, the company believes that neutralizing titer levels with B.1.351 are still high enough to be protective. However, they plan to produce a vaccine booster targeted at the SA variant and begin a Phase 1 study of that booster within the next several months. [January 25]
  • Vaccine approved for Emergency Use in the US[7] [December 18], Canada[39] [December 23], EU[40] [January 6], and the UK[41] [January 8].
  • Phase 3 trial final results reported in a company press release showed vaccine efficacy of 94.1% against infection and 100% against severe COVID-19.[42] Results have not yet been published in a peer-reviewed journal. Final analysis performed after 196 COVID-19 were confirmed. Remarkably, 30 severe cases were observed — all in the placebo group and none in the vaccine group. Efficacy was consistent across age, race and ethnicity, and gender demographics. No serious side effects were observed. [November 30]
  • Phase 3 study interim results reported in a company press release showed reduction of COVID-19 infection by 95% in vaccine recipients.[43] Results have not yet been published in a peer-reviewed journal. Study enrolled more than 30,000 participants to date and the first interim efficacy analysis was conducted when 95 COVID-19 cases were confirmed beginning two weeks after the second dose. Of these cases, 90 cases of COVID-19 were observed in the placebo group versus 5 in the vaccine group. Eleven severe cases were reported – all 11 cases occurred in the placebo group and none in the vaccine group. No serious side effects were reported. The trial is continuing to enroll and is expected to continue through the final analysis. [November 16]
  • Results of Phase 1 clinical trial in older adults (56+ years of age) published in the New England Journal of Medicine[44] showed a robust antibody and cellular immune response in vaccinated individuals. Mild-moderate side effects were common but self-limited. [September 29]
  • Preclinical study in non-human primates reported in New England Journal of Medicine.[45] Two injections elicited high levels of neutralizing antibody and Th1 CD4 T-cell responses in rhesus macaques. Two days after challenge of vaccinated animals with intranasal and intratracheal virus, viral replication was undetectable in bronchoalveolar-lavage fluid and nasal secretions. [July 28]
  • Phase 1 study published in NEJM.[46] Forty-five adults age 18–55 were tested with one of three dose levels given as 2 vaccinations 28 days apart. All subjects produced antibodies and neutralizing activity on par with natural infection. Mild-moderate side effects were common. [July 14]
• INOVIO INO-4800 vaccine
  • Phase 2/3 has been put on partial clinical hold until questions posed by the U.S. FDA about the candidate and the delivery device (CELLECTRA® 2000) have been satisfactorily addressed. This hold is not due to the occurrence of any adverse events. [September 28]
  • Reports in a press release success of DNA-based vaccine INO-4800 in Phase 1 trial.[47][June 30]
• Wuhan Institute of Biological Products / Sinopharm β-propiolactone-inactivated-whole-virus vaccine
  
  • Interim analysis of a Phase 1/2 trial reported in JAMA[48] showed that in 225 healthy adults aged 18–59 two injections of a medium dose spaced 21 days apart generated the most neutralizing and specific IgG antibodies and those levels were reported to be comparable to other vaccine candidates (but no direct comparisons was made to those vaccines or to convalescent plasma). Side effects were mild, self-limited and lower in frequency than what has been reported for other vaccine types. [August 13]
• CanSino Biologics Adenovirus Type 5 vectored vaccine
  • Phase 2 trial published in Lancet[49] showed that in 382 adults age ≥ 18 a single dose induced cellular or humoral immune responses at day 28 post vaccination in 91–95% of recipients depending on the dose. Mild-moderate side effects were common; Grade 3 adverse effects were seen in 9%. [July 20]
  • Received Military Specially-needed Drug Approval (軍隊特需藥品批件) for non-replicating adenovirus vaccine Ad5-nCoV for use in the Chinese military.[50][June 25]

Pfizer / BioNTech
BNT162b2, Tozinameran, Comirnaty

44k

95%[51]

UK: 2-Dec[5]
CA: 9-Dec[6]

US: 11-Dec[7]

EU: 22-Dec[8]

2

21

mRNA

-70ºC

Moderna
mRNA-1273

30k

94%[52]

US: 18-Dec[53]

CA: 23-Dec[39]

EU: 06-Jan[40]

UK: 08-Jan[41]

2

28

mRNA

2–8ºC

AstraZeneca / Oxford
AZD1222

24k

67%[18],[15]

UK: 30-Dec[16]

AR: 30-Dec

IN: 03-Jan

MX: 04-Jan

BR: 17-Jan

EU: 29-Jan[17]

2

28

Adenovirus

2–8ºC

Gamaleya Research Institute
Gam-COVID-Vac (Sputnik V)

20k

92%[26]

RU: 11-Aug[54]
MX: 03-Feb

2

21

Adenovirus

-18ºC

Sinovac
CoronaVac

26k

50%[55], 79%[56]

CN: 29-Dec

2

14

Inactivated

2–8ºC

Johnson & Johnson
Ad26.COV2.S, JNJ-78436735

44k

66% (prelim)[29]

1

-

Adenovirus

2–8ºC

Novavax
NVX-CoV2373

15k

89% (prelim)[34]

2

21

Protein Subunit

2–8ºC

Sinopharm
Inactivated virus, BBIBP-CorV

50k

2

21

Inactivated

Bharat Biotech
BBV152

25k

Not yet reported

IN: 03-Jan

2

14

Inactivated

CanSino Biologics
Ad5-nCoV

40k

1

-

Adenovirus

2–8ºC

CureVac AG
CVnCoV

2

28

Protein Subunit

Trial = # of Phase 3 trial participants; Phase 3 Efficacy = Vaccine Efficacy/Effectiveness (reduction in disease among the vaccinated group); Emergency Approval = Date of Emergency Use Authorization (EUA); # = Number of Doses Required; US = United States; UK = United Kingdom; CA = Canada; EU = European Union; AR = Argentina; IN = India; MX = Mexico; CN = China; BR = Brazil

Recipient of U.S. Operation Warp Speed Funding

Pfizer / BioNTech/
BNT162

NCT04368728
Results in NEJM[57]

NCT04537949
Results in Nature[12]

NCT04537949
Positive final results.[10],[9]

Moderna/ NIAID
mRNA-1273

NCT04283461
Results in NEJM[46],[44]

NCT04405076

NCT04470427

Positive final results.[43],[42]

University of Oxford/ AstraZeneca
AZD1222

NCT04324606
Results in Lancet[58]

NCT04516746
Positive interim results.[19]

Sinovac
CoronaVac

NCT04383574
NCT04352608
Results in Science[59]

NCT04456595

Wuhan Institute of Biological Products/ Sinopharm
Inactivated virus

ChiCTR-2000031809
Results in JAMA[48]

ChiCTR-2000034780

Beijing Institute of Biological Products/ Sinopharm
BBIBP-CorV

ChiCTR-2000032459
Results in Lancet Infect Dis[60]

ChiCTR-2000034780

Bharat Biotech
BBV152

CTRI/2020/07/026300

CTRI-2020/11/028976

CanSino Biological Inc/ Beijing Institute of Biotechnology
Ad5-nCoV

NCT04313127
Results in Lancet[61]

NCT04341389
Results in Lancet[49]

NCT04526990; NCT04540419

Gamaleya Research Institute
Gam-COVID-Vac, Sputnik V

NCT04437875;
Results in Lancet[27]

NCT04587219

NCT04530396

Janssen Pharmaceutical Companies
Ad26.COV2.S

NCT04436276

NCT04505722

Novavax
NVX-CoV2373

NCT04368988
Results in NEJM[36]

2020-004123-16

*Trials spanning Phase 1 and 2 represent Phase 1/2 trials.

Moderna/ NIAID

RNA

LNP-encapsulated mRNA (mRNA-1273)

Phase 3 NCT04470427; Positive final results.[43],[42]

Phase 2 NCT04405076

Phase 1 NCT04283461; Results in NEJM[46],[44]

BioNTech/ Fosun Pharma/ Pfizer

RNA

3 LNP-mRNAs (BNT162)

Phase 3 NCT04368728; Positive final results.[10],[9]

Phase 1/2 NCT04537949; Results in Nature[12]

University of Oxford/ AstraZeneca

Non-Replicating Viral Vector

Weakened adenovirus (ChAdOx1-S; AZD1222)

Phase 3 NCT04516746; Positive interim results.[19]

Phase2b/3 NCT04400838

Phase 1/2 PACTR202006922165132; 2020-001072-15; Results in Lancet[61]

Sinovac

Inactivated

Inactivated + alum (CoronaVac; formerly PiCoVacc)

Phase 3 NCT04456595

Phase 1/2 NCT04383574 ; NCT04352608; Results in Science[59]

Wuhan Institute of Biological Products/ Sinopharm

Inactivated

Inactivated

Phase 3 ChiCTR2000034780

Phase 1/2 ChiCTR2000031809; Results in JAMA[48]

Beijing Institute of Biological Products/ Sinopharm

Inactivated

Inactivated (BBIBP-CorV)

Phase 3 ChiCTR2000034780

Phase 1/2 ChiCTR2000032459

CanSino Biological Inc./ Beijing Institute of Biotechnology

Non-Replicating Viral Vector

Adenovirus Type 5 Vector (Ad5-nCoV)

Phase 3 NCT04526990; NCT04540419

Phase 2 NCT04341389; Results in Lancet[49]

Phase 1 NCT04313127; Results in Lancet[61]

Gamaleya Research Institute

Non-Replicating Viral Vector

Adenovirus-based (Gam-COVID-Vac; Гам-КОВИД-Вак)

Phase 3 NCT04530396

Phase 1 NCT04436471; NCT04437875; Results in Lancet[27]

Anhui Zhifei Longcom Biopharmaceutical/ Institute of Microbiology, Chinese Academy of Sciences

Protein Subunit

Adjuvanted recombinant protein (RBD-Dimer)

Phase 2 NCT04466085

Phase 1 NCT04445194

Inovio Pharmaceuticals / International Vaccine Institute

DNA

DNA plasmid vaccine with electroporation (INO-4800)

Phase 1/2 NCT04336410; NCT04447781

Novavax

Protein Subunit

Recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M (NVX-CoV2373)

Phase 3 2020-004123-16

Phase 2b NCT04533399

Phase 1/2 NCT04368988; Results in NEJM[36]

Janssen Pharmaceutical Companies

Non-Replicating Viral Vector

Ad26.COV2.S

Phase 3 NCT04505722

Phase 1/2 NCT04436276

Bharat Biotech

Inactivated

Whole-Virion Inactivated

Phase 1/2 CTRI/2020/07/026300

Kentucky Bioprocessing, Inc

Protein Subunit

RBD-based

Phase 1/2 NCT04473690

Institute of Medical Biology, Chinese Academy of Medical Sciences

Inactivated

Inactivated

Phase 1/2 NCT04470609

Phase 1 NCT04412538

Sanofi Pasteur/GSK

Protein Subunit

S protein (baculovirus production

Phase 1/2 NCT04537208

Research Institute for Biological Safety Problems, Rep of Kazakhstan

Inactivated

Inactivated

Phase 1/2 NCT04530357

SpyBiotech/Serum Institute of India

VLP

RBD-HBsAg VLPs

Phase 1/2 ACTRN12620000817943

Genexine Consortium

DNA

DNA Vaccine (GX-19)

Phase 1 NCT04445389

Cadila Healthcare Limited

DNA

DNA plasmid vaccine

Phase 1/2 CTRI/2020/07/026352

Osaka University/ AnGes/ Takara Bio

DNA

DNA plasmid vaccine + Adjuvant

Phase 1 JapicCTI-205328

Gamaleya Research Institute

Non-Replicating Viral Vector

Adenovirus-based (Gam-COVID-Vac; Гам-КОВИД-Вак)

Phase 1 NCT04436471; NCT04437875

Clover Biopharmaceuticals Inc./ GSK/ Dynavax

Protein Subunit

Native like Trimeric subunit Spike Protein vaccine (SCB-2019)

Phase 1 NCT04437875

Arcturus/Duke-NUS

RNA

mRNA

Phase 1/2 NCT04480957

Vaxine Pty Ltd/ Medytox

Protein Subunit

Recombinant spike protein with Advax™ adjuvant

Phase 1 NCT04453852

University of Queensland/ CSL/ Seqirus

Protein Subunit

Molecular clamp stabilized Spike protein with MF59 adjuvant

Phase 1 ACTRN12620000674932p

Imperial College London

RNA

LNP-nCoVsaRNA

Phase 1 ISRCTN17072692

Curevac

RNA

mRNA

Phase 1 NCT04449276

Medigen Vaccine Biologics Corporation/ NIAID/ Dynavax

Protein Subunit

S-2P protein + CpG 1018

Phase 1 NCT04487210

People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech

RNA

mRNA

Phase 1 ChiCTR2000034112

Medicago Inc./ Université Laval

VLP

Plant-derived VLP

Phase 1 NCT04450004

Institute Pasteur/ Themis/ Univ. of Pittsburg CVR/ Merck Sharp & Dohme

Replicating Viral Vector

Measles-vector based

Phase 1 NCT04497298

ReiThera/ LEUKOCARE/ Univercells

Non-Replicating Viral Vector

Replication defective Simian Adenovirus (GRAd) encoding S

Phase 1 NCT04528641

Instituto Finlay de Vacunas, Cuba

Protein Subunit

RBD + Adjuvant

Phase 1 IFV/COR/04

FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo

Protein Subunit

Peptide

Phase 1 NCT04527575

West China Hospital, Sichuan University

Protein Subunit

RBD (baculovirus production expressed in Sf9 cells)

Phase 1 ChiCTR2000037518

University Hospital Tuebingen

Protein Subunit

SARS-CoV-2 HLA-DR peptides

Phase 1 NCT04546841

COVAXX

Protein Subunit

S1-RBD-protein

Phase 1 NCT04497298

Beijing Wantai Biological Pharmacy/ Xiamen University

Replicating Viral Vector

Intranasal flu-based-RBD

Phase 1 ChiCTR2000037782

Vaxart

Non-Replicating Viral Vector

Ad5 adjuvanted Oral Vaccine platform

Phase 1 NCT04563702

Ludwig-Maximilians - University of Munich

Non-Replicating Viral Vector

MVA-SARS-2-S

Phase 1 NCT04569383

^†Adapted from Draft landscape of COVID-19 candidate vaccines. WHO. 22 December 2020.[1]

LNP = lipid nanoparticle; RBD = receptor-binding domain; mRNA = messenger RNA; VLP = virus-like particles

Recipient of U.S. Operation Warp Speed Funding[62],[63]